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The involvement of mitochondria and the caspase-9 activation pathway in rituximab-induced apoptosis in FL cells. 2009

Jonna Eeva, and Ulla Nuutinen, and Antti Ropponen, and Mikko Mättö, and Mine Eray, and Riikka Pellinen, and Jarmo Wahlfors, and Jukka Pelkonen
Department of Clinical Microbiology, University of Kuopio, Yliopistoranta 1C, 70210, Kuopio, Finland. eeva@hytti.uku.fi

Despite the wide use of anti-CD20 antibody rituximab in the cancer treatment of B cell malignancies, the signalling pathways of CD20-induced apoptosis are still not understood. By using dominant negative (DN)-caspase-9 overexpressing follicular lymphoma cells we demonstrated that the activation of caspase-9 was essential for rituximab-mediated apoptosis. The death receptor pathway mediated by caspase-8 activation was not involved in rituximab-mediated apoptosis since overexpression of FLIP(short) or FLIP(long) proteins, inhibitors of caspase-8 activation, could not inhibit rituximab-induced apoptosis. However, the death receptor pathway activation by anti-Fas antibodies showed an additive effect on rituximab-induced apoptosis. The stabilisation of the mitochondrial outer membrane by Bcl-x(L) overexpression inhibited cell death, showing the important role of mitochondria in rituximab-induced apoptosis. Interestingly, the rituximab-induced release of cytochrome c and collapse of mitochondrial membrane potential were regulated by caspase-9. We suggest that caspase-9 and downstream caspases may feed back to mitochondria to amplify mitochondrial disruption during intrinsic apoptosis.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008224 Lymphoma, Follicular Malignant lymphoma in which the lymphomatous cells are clustered into identifiable nodules within the LYMPH NODES. The nodules resemble to some extent the GERMINAL CENTER of lymph node follicles and most likely represent neoplastic proliferation of lymph node-derived follicular center B-LYMPHOCYTES. Brill-Symmers Disease,Follicular Lymphoma,Lymphoma, Giant Follicular,Lymphoma, Nodular,Follicular Large-Cell Lymphoma,Follicular Lymphoma, Giant,Follicular Lymphoma, Grade 1,Follicular Lymphoma, Grade 2,Follicular Lymphoma, Grade 3,Follicular Mixed-Cell Lymphoma,Giant Follicular Lymphoma,Histiocytic Lymphoma, Nodular,Large Lymphoid Lymphoma, Nodular,Large-Cell Lymphoma, Follicular,Lymphocytic Lymphoma, Nodular, Poorly Differentiated,Lymphocytic Lymphoma, Nodular, Poorly-Differentiated,Lymphoma, Follicular Large-Cell,Lymphoma, Follicular, Grade 1,Lymphoma, Follicular, Grade 2,Lymphoma, Follicular, Grade 3,Lymphoma, Follicular, Mixed Cell,Lymphoma, Follicular, Mixed Lymphocytic-Histiocytic,Lymphoma, Follicular, Mixed Small and Large Lymphoid,Lymphoma, Follicular, Small and Large Cleaved Cell,Lymphoma, Follicular, Small and Large Cleaved-Cell,Lymphoma, Histiocytic, Nodular,Lymphoma, Large Cell, Follicular,Lymphoma, Large Lymphoid, Nodular,Lymphoma, Large-Cell, Follicular,Lymphoma, Lymphocytic, Nodular, Poorly Differentiated,Lymphoma, Lymphocytic, Nodular, Poorly-Differentiated,Lymphoma, Mixed-Cell, Follicular,Lymphoma, Nodular, Large Follicular Center Cell,Lymphoma, Nodular, Large Follicular Center-Cell,Lymphoma, Nodular, Mixed Lymphocytic Histiocytic,Lymphoma, Nodular, Mixed Lymphocytic-Histiocytic,Lymphoma, Nodular, Mixed Small and Large Cell,Lymphoma, Small Cleaved Cell, Follicular,Lymphoma, Small Cleaved-Cell, Follicular,Lymphoma, Small Follicular Center-Cell,Lymphoma, Small Lymphoid, Follicular,Mixed-Cell Lymphoma, Follicular,Nodular Large Follicular Center-Cell Lymphoma,Small Cleaved-Cell Lymphoma, Follicular,Small Follicular Center-Cell Lymphoma,Brill Symmers Disease,Disease, Brill-Symmers,Follicular Large Cell Lymphoma,Follicular Large-Cell Lymphomas,Follicular Lymphomas,Follicular Lymphomas, Giant,Follicular Mixed Cell Lymphoma,Follicular Mixed-Cell Lymphomas,Giant Follicular Lymphomas,Histiocytic Lymphomas, Nodular,Large Cell Lymphoma, Follicular,Large-Cell Lymphomas, Follicular,Lymphoma, Follicular Large Cell,Lymphoma, Follicular Mixed-Cell,Lymphoma, Nodular Histiocytic,Lymphoma, Small Follicular Center Cell,Lymphomas, Follicular,Lymphomas, Follicular Large-Cell,Lymphomas, Follicular Mixed-Cell,Lymphomas, Giant Follicular,Lymphomas, Nodular,Lymphomas, Nodular Histiocytic,Mixed Cell Lymphoma, Follicular,Mixed-Cell Lymphomas, Follicular,Nodular Histiocytic Lymphoma,Nodular Histiocytic Lymphomas,Nodular Large Follicular Center Cell Lymphoma,Nodular Lymphoma,Nodular Lymphomas,Small Cleaved Cell Lymphoma, Follicular,Small Follicular Center Cell Lymphoma
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000069283 Rituximab A murine-derived monoclonal antibody and ANTINEOPLASTIC AGENT that binds specifically to the CD20 ANTIGEN and is used in the treatment of LEUKEMIA; LYMPHOMA and RHEUMATOID ARTHRITIS. CD20 Antibody, Rituximab,GP2013,IDEC-C2B8,IDEC-C2B8 Antibody,Mabthera,Rituxan,IDEC C2B8,IDEC C2B8 Antibody,Rituximab CD20 Antibody
D000911 Antibodies, Monoclonal Antibodies produced by a single clone of cells. Monoclonal Antibodies,Monoclonal Antibody,Antibody, Monoclonal
D017209 Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, i.e., DNA FRAGMENTATION. It is genetically programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Apoptosis, Extrinsic Pathway,Apoptosis, Intrinsic Pathway,Caspase-Dependent Apoptosis,Classic Apoptosis,Classical Apoptosis,Programmed Cell Death,Programmed Cell Death, Type I,Apoptoses, Extrinsic Pathway,Apoptoses, Intrinsic Pathway,Apoptosis, Caspase-Dependent,Apoptosis, Classic,Apoptosis, Classical,Caspase Dependent Apoptosis,Cell Death, Programmed,Classic Apoptoses,Extrinsic Pathway Apoptoses,Extrinsic Pathway Apoptosis,Intrinsic Pathway Apoptoses,Intrinsic Pathway Apoptosis
D045304 Cytochromes c Cytochromes of the c type that are found in eukaryotic MITOCHONDRIA. They serve as redox intermediates that accept electrons from MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX III and transfer them to MITOCHONDRIAL ELECTRON TRANSPORT COMPLEX IV. Cytochrome c,Ferricytochrome c,Ferrocytochrome c,Apocytochrome C
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines

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